CA1079734A - 1-(3,3,3,-triarylpropyl)-4-phenyl-4-piperidinemethanols - Google Patents
1-(3,3,3,-triarylpropyl)-4-phenyl-4-piperidinemethanolsInfo
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- CA1079734A CA1079734A CA250,373A CA250373A CA1079734A CA 1079734 A CA1079734 A CA 1079734A CA 250373 A CA250373 A CA 250373A CA 1079734 A CA1079734 A CA 1079734A
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- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
- C07D211/64—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4 having an aryl radical as the second substituent in position 4
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- C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
- C07D211/96—Sulfur atom
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- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/08—Hydrogen atoms or radicals containing only hydrogen and carbon atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention is concerned with 1-(3,3,3-triarylpropyl)-4-phenyl-4-piperidinemethanols.
These compounds are prepared by reacting the appropriate piperidine esters or piperidine ester-amideswith a suitable hydride reducing agent in an organic solvent to give the compounds of the instant invention. The compounds of the instant invention possess potent anti-diarrheal utility as evidenced by their ability to inhibit gastro-lntestinal motility. These subject compounds also possess a very low degree of analgesia.
The present invention is concerned with 1-(3,3,3-triarylpropyl)-4-phenyl-4-piperidinemethanols.
These compounds are prepared by reacting the appropriate piperidine esters or piperidine ester-amideswith a suitable hydride reducing agent in an organic solvent to give the compounds of the instant invention. The compounds of the instant invention possess potent anti-diarrheal utility as evidenced by their ability to inhibit gastro-lntestinal motility. These subject compounds also possess a very low degree of analgesia.
Description
9~3~
1-(3,3,3-TRIARYLPROPYL)-4-PI-IENYL-4-PIPERIDINEMETHANOLS
The preient invention relates to compounds of the general formula Ar"
/~\ ~CH20R
Ar'-C-(Alk)-N ~ \ (I) Ar ~
and acid addikion salts thereo~ wherein the Alk ls straight or branched chain alkylene containing 2-l~ carbon atoms; Ar and Ar' are phenyl, alkyl substituted phenyl wherein the alkyl radical contains from 1-4 carbon atoms or halo substituted phenyl; Ar" is phenyl, alkyl sub-stituted phenyl wherein the alkyl radical contains 1-4 lO carbon atoms, halo substituted phenyl, pyridyl or thi.enyl; X i8 hydrogn, halogen or an alkyl radical contalning from 1 to 4 carbon atomEi; R is hydrogenlan alkyl radical containing from 1 to 4 carbon atoms or an alkanoyl radlcal containing from 2-5 carbon atoms. -The alkylene radicals encompassed by the term Alk are exempli~ied by ethylene, propylene, or tri-methylene. The term alkyl radical is exemplified by methyl, ethyl, propyl and butyl. The term alkanoyl . ~ ,' .~
'9734 radical ls exemplified by ethanoyl, propanoyl, butanoyl, and pentanoyl. The term halogen is exempl:Lfied by fluoro, chloro, bromo, or iodo.
The organic bases of this invention form non-toxic acid-addition salts with a variety o:~ organic and inorganic acids. Such salts are formed with acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydri-odic, sulfamic, cltric, lactic, maleic, mallc, succinic~ .
tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic :
and related acids.
The compounds o~ the present lnventlon can be ; :
conveniently prepared by reactin~ a compound o~ the ~cneral formula Ar" -O(Alkyl) Ar'-7~(Alk) ~ . (II) Ar >~ ' ' X/ .:
Il - .
wherein Alk is defined as above or is -Alk'-C-wherein the free valence of the carbonyl is attached to the nitrogen and Alk' is alkylene of 1 to 3 carbon atoms, Alkyl is a radical of 1 to 4 carbon atoms, Ar, Ar', Ar" and X are defined as above with a suitable re-ducing agent in the presence of an organic solvent to 10~973~
give a compound of the general formula Ar"
~ ~C~120 Ar'-C-(Alk)-N
lr ~ (III) X -~ ' wherein Alk, Ar, Ar', Ar" and X are de.~:lned as be~ore wlth the prov:Lso that a) when the compounds of ~ormula I ln whlch R is an alkanoyl radical are desired the .
compounds of formula III are esterified with .
a suitable anhydride in a basic medium to :
give the desired esters of formula I and : .
b) when the compounds of formula I in which R is an alkyl radical are desired.the .
compounds of formula III can be treated with sodium hydride in a sultable solvent and then further treated with an alkyl halide to give the desired ethers of formula I.
Reducing agents suitable for the practice of -this invention are hydrides reducing agents such as lithium aluminum hydride, dissobutylaluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride. A parti-cularly preferred reduing agent is lithium aluminum :
hydride. Organic solvents which are useful for the _L~_ :
. , ,' , ~L079~34 practice of this inventlon are tetrahydrofuran, ethyl ether, 1,2-dimethoxyethane and diglyme (the dimethyl ether of diethylene glycol). Tetrahydrofuran is a preferred . solvent.
An alternate process for the preparation of the compounds of this invention comprises reacting a compound of the formula Ar"
Ar'-C-(Alk)-~
Ar whereln Alk, Ar, Ar', Ar" are defined as before and Z is chlorine or bromine with a compound of the ~eneral for-mula H- ~ ~r~ C~120R
'.
~ .
X '' :-wherein R and X are defined as before in a suitable inert solvent such as toluene, benzene, methylene chloride, 4-methyl-2-pentanone or cyclohexane in the presence of an acid acceptor such as triethylamine or potassium carbo-, . . .
g73~
nate to give the compounds of formula I.
Another process for the preparation ofcompounds of the present invention whereln R of formula I is alkyl or alkanoyl comprises reacting acompound of the general formula Ar"
Ar'-lC-H
Ar where:Ln Ar, Ar~ and Ar" are de~lned as be~ore with n-butyl lithium ln a suitable organic solvent and further re-acting this mixture with a compound of the general formula /--\ / CH20R ' Z-(Alk)-DI~
wherein Alk and X are defined as before and Z is chlorine or bromine and R' is alkyl or alkanoyl to give the compounds of formula I wherein R is alkyl or alkanoyl. :-The compounds of the present invention possess valuable pharmocological properties. They are potent :
anti-diarrheal agents which show little or no analgesia .
107973~
.' ~ !
activity. -Anti-diarrheal utility of the instant compounds is evidenced by their abllity to inhibit gastrointestinal motility as set out in the following tests.
Charcoal Meal Test The method used in the present study has been adapted from techniques previously described (Macht and Barba-Gose, 1931, Janssen and Jageneau, 1957 Sanvordeher and Da~ani, 1975) Male Charles River mice (20-25 g, n=6) prevlously fasted for 2ll hours were ~r~treated with the t;est. compounds aclm:~n:lstered or-ally as a solution ln water or ~uspended :lrl 0.5% rnethyl oellulose.
A constant volume of 10 ml/kg was employed. Thirty minutes following administration of the test compounds, the animals were given a single oral dose of charcoal (0.2 ml per mouse of a 10% charcoal suspended in 1.0%
methyl cellulose). Three and a half hours after char-coal administration, the animals were sacrificed and the cecum examined for the absence or presence of charcoal on an all-or-none basis.
The median effective *ose (ED50) was cal-culated for each compound using the logistic method of Berkson (1953).
.
73~
Castcr Oil Induced Diarrhea in the ~at -Adult Charles River male rats were fasted in community cages for 24 hours prior to the test, with free access to water. The compound was administered intra-gastrically (suspende~ on 0.5% methyl cellulose) onehour prior to the administration of castor oil at the dose of 1.0 ml/rat intragastrically. The rats were then observed for the presence or absence of diarrhea, at hourly intervals for up to 8 hours past administration of castor oll. The median effective dose values at each hourly lnterval was calculated rOr the compound us~ng the me~hod o~ Berk~on (1953). When kestecl .In the above procedures l-(3,3,3-trlphenylpropyl)-l~-phenyl-4-piperi-dinemethanol was found to be very active in its ability to inhibit gastrointestinal motility.
The assessment of the analgesic effect of the instant compounds was conducted in the mouse hot plate and tail clip tests.
Mouse ~lot Plate Test A mouse (adult male weighing 18-25 grams) is placed in a restraining cylinder on a hot plate with the temperature controlled at 55 + 0.3C. The reaction time of the mouse to lick a foot or jump is measured at 60, 40 and 20 minutes before and 30, 60, 90, and 120 minutes after administration of the test compound. The "normal" reaction time is measured as the median of the ;
three pretreatment reaction times. A positive response - , .
consists of a reaction time greater than twice the normal time at any of the post treatment times. A dose Or the test compound is considered active when 50 per cent or more of the animals used show a positive response.
~;
Tail Cli~ Test ; A special clip is applied to the base of the tail of the mouse (adult male weighing 18-25 grams) and the time for the animal to turn around to bite at it is , 10 measured. The sensitivity of each mouse is determined '~ one-half hour prlor to dru~ admin.~stratLon. On:ly tho~e mlce attempt:lng to blte the c.l:lp are lncludecl ln the experiment. The test compound is then administered intraperitoneally and the response to placement of the clip is determined at 30, 60, 90, and 120 minutes after treatment. A response is consldered positive if the , animal takes more than 2 times the pre-drug time to i bite at the clip at any of these time intervals. A
test compound i8 considered active when 50 percent or more of the animals used show a posit:lve response.
when tested in the above procedures l-(3,3,3-triphenyl-propyl)-4-phenyl-4-piperidinemethanol showed very little analgesic effect. .-The following examples describe in detail compounds illustrative of the present invention and methods for their preparation. Throughout the examples hereinafter set forth, temperatures are given in degrees ., Centigrade and relative amounts of materlals in parts _g_ ~C:i 7~734 :
by wei~ht, except as otherwise noted. ~
' EXAMPLE I
- A mixture o~ 2 parts o~ triphenylcarbinol and 8 parts of malonic acid were heated at 170 for 31 hours.
This mixture was cooled and then dissolved in hot ethanol. 3,3,3-Triphenylpropionic acid, melting at 182, crystallized from the ethanol upon cooling. 1 Part of 3,3,3-trlphenylpropionic acid was then refluxed with 5 parts of thionyl chloride for 4 hours and the excess thionyl chloride was removed ln vacuum to provide the crud~ 3,3,3-trlphenylpropionyl chloride. 9 Parts o~
thl~ 3,3,3-trlphenylprop:lonyl chlorlde was then reacted with 27.0 parts o~ ethyl 4-phenyl-4 plperidinecarboxylic acid in the presence of 4 parts of triethylamine in benzene. The resulting amide was reduced with 5 parts of lithium aluminum hydride in ether at reflux ~or 2.5 hours. The reaction mixture was cooled and treated with 15% aqueous sodium hydroxide solution to decompose any unreacted lithium aluminum hydride. The reaction mlxture was then filtered and washed wlth ether. The ether solution was evaporated to give an oil. This oil was then slurried in lO~HCl and partitioned between the ~
acid and ether. The aqueous phase which contained an -~ ~;
insoluble oil was extracted with methylene chloride and dried over anhydrous sodium sulfate. Evaporation of this methylene chloride solution gave a solid which was taken up in acetone and precipitated with ether to give 1 (3,3,3-triphenylpropyl)-4-(4-phenyl)-l~-piperidine-, ~7973~
methanol hydrochloride, melting at about 256-259C.
Substitutlon of 2 parts of (p-chlorophenyl) diphenyl methanol for the triphenylcarbinol used above and substantial repetition of the foregoing procedure afforded 1-[3-(p-chlorophenyl)-3,3-diphenylpropyl~-4-(4-phenyl)-4-piperidinemethanol hydrochloride.
Substitution of 2 parts of l,l-diphenyl-l-(p-tolyl)methanol for the triphenylcarbinol used above and substantial repetition of the procedure of Example I afforded 1-[3-(p-tolyl)-3,3-diphenylpropyl~
phenyl)-l~-piperidlnemethanol hydrochlor:Lde.
F.XAMPLE 2 A mixture of 18.9 parts of ethyl ~I-phenyl-L~-piperidinecarboxylic acid, 81.1 parts of 4-methyl-2-pentanone, 7.2 parts of ethylene oxide and 40 parts ofmethanol was heated in a citric bottle at about 65C.
~or 3 days. The resulting solution was cooled, the solvent was evaporated under reduced pressure and the resldual material was partitioned between water and methylene chloride. The methylene chloride layer was then separated and dried and the solvent evaporated under reduced pressure. The resulting residue was then par-titioned between dilute hydrochloric acid and ether.
The acid layer was then made alkaline with aqueous sodium hydroxide and the resultlng mixture was extracted with ether. The ether was dried over sodium sulfate and potassium carbonate and concentrated before it was ~inally diluted with pentane. The precipitate which , 1~7973~ ~
formed was separated by filtration, washed and then dried and then finally recrystallized from hexane to give 1-(2-hydroxyethyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester melting at about 82-85C.
A solution was prepared from 9.1 parts of the ester obtained in the preceding paragraph and 330 parts of methylene chloride. This solution was saturated with hydrogen chloride gas at ice bath temperature and ~ parts of thionyl chloride was added. The mixture was re-fluxed for 75 minutes and then cooled and volatile materlal was removed under reduced pressure. The result-lng resiclual sol:ld was washed w-Lth benzene, dr:Le~ ln air ancl then recryst~ d ~rom a m:Lxture Or ethanol ~nd ether to give 1-(2-chloroethyl)-4-phenyl-4-piperidine-carboxylic acid ethyl ester hydrochloride melting atabout 208-213C. To a solution of 3.l~ parts of diphenyl-2-pyridylmethane in 100 parts of cyclohexane was added, at 10-15C. under nitrogen, 8 parts by volume of a 2 molar solution of butyllithium in hexane.
This solution was stlrred at room temperature ~or 30 minutes and th~n a solution of ethyl 1-(2-chloroethyl)-4-phenyl-ll-piperidinecarboxylate, obtained from 4 7 parts of the corresponding hydrochloric salts, in 24 parts of `
cyclohexane was added and the mixture was refluxed with stirring for 3 hours. The resulting solution was cooled, diluted with 105 parts of ether and then washed with aqueous sodium hydroxide solution. The organic solu-tion was then dried and the solvent evaporated under reduced pressure to leave a residual red-brown gum which 1~7973~
solidified. This was washed with pentane and then air dried to give crude ethyl l-[3,3-diphenDl-3-(2-pyridyl)propyl]-4-phenyl-4-piperidinecarboxylate. A
mixture of 3.ll parts of this crude ester and o.8~ part of lithium aluminum hydride in 87 parts of ether was heated and stirred under nitrogen ror 1.3 hours. The mixture was then decomposed by the successive addition of 0.9 part of water, 0.7 part of aqueous sodium hydroxide solu-tion, and 3.2 parts of water. The mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residual material was washed with pentane and then dissolved in 250 parts of boiling ebher-. ~his was concentrated to a smallv~ume and cooled and ~he solid which rormed was separated by E`lltratlon and recrystalli~ed twice ~rom ether to ~,ive 1-[3,3-diphenyl-3-(2-pyridyl)propyl]-4-phenyl-4-piperidinemethanol melting at about 148-15QC.
A mixture of 1 part of 1-(3,3,3-triphenyl-propyl)-4-phenyl-ll-piperidinemethanol hydrochloride, 10 parts of pyridine and 3.2 parts of acetic anhydrlde was allowed to stand for 24 hours. Volatile material was removed under reduced pressure and the resulting residue was partitioned between dilute sodium hydroxide and ether. The ether layer was separated, washed with water, dried over sodium sulfate and then treated with an excess of a solution of hydrogen chloride in 2-propanol.
The solid which formed was separated by filtration and : , . .
79'73~
then washed successively with ether, water, and ether, and then air dried to give l-(3,3,3-triphenylpropyl)-4-phenyl-4-acetoxymethylpiperidine hydrochloride melting at about 210-213C.
, EXAMpLE ll A solution of 3 parts of 1-(3,3,3-triphenyl-propyl)-4-phenyl-4-piperidinemethanol (obtained from the corresponding hydrochlorlde salt), 0.35 parts of sodium hydride as a 50% suspension in mineral oil, and 70 parts by volume of 1,2-dimethoxyethane were heated at 37-39C. ~or 1.5 hours under nitrogen wlth st:l.rrlrl~.
The rnlxture was cooled to room temper-a~ure and ~.9 part of' methyl iodide was added and the mixture was stirred at room temperature for 20 hours. The solvent was eva-porated under reduced pressure and the residue was tri-turated with ether. The resulting solid was then separated by filtration, dissolved in ether and treated with an excess of hydrogen chloride in 2-propanol.
The solid which formed was separated by filtration, washed wlth ether, and alr dr:led and then f`urther recrystallized from a mixture of methanol and ether to give 1-~3,3,3-tri-phenylpropyl)-4-phenyl-4-methoxymethylpiperidine hydro-chloride melting at about 212-213.5C.
.
:
.
~07973~L
EX~MPL~ 5 A mixture of 63.7 parts Or bls-2-chloroethyl-amine hydrochloride, 67.~ parts of 4-toluenesulphonyl chloride and 955 parts of methylene chloride was cooled in an ice bath and then 356 parts by volume of a 2 N
aqueous sodium hydroxide solution was added with stirring at 5~~C. The mixture was stirred at 5-8C.
for 3 hours and then at room temperature for 18 hours.
The organic layer was separated and washed successively with dilute hydrochloric acid, water, dilute potassium carbonate solution, and water and then dried over sodlum ~,ulfate. The solvent was then evapora~ed under reduced pressure and the rosldual o:Ll was crystalll~.ed from methanol to ~ive N,N-bis(2-chloroethyl)~ll-toluene-sulfonamide melting at about 45-ll7C.
To a solution of 60 parts of 4-chlorophenylaceto-nitrile and ll~ parts of N,N-bis(2-chloroethyl)-4-toluenesulfonamide in 720 parts of dried benzene, there was added portionwise with stirring at 10-13C., 32.6 parts of sodamide. The cooling bath was then removed and the mlxture was stirred ~or one hour during which tlme the temperature rose to 70C. and then fell back to 43C-Ice cold water was added to the mixture and a fine solid formed. This was separated by filtration and washed successively with water and benzene and dried and then triturated in boiling methanol. The undissolved solid was separated by filtration, washed with water and dried to give 1-(4-toluenesulfonyl)-4-(4-chlorophenyl)-4-piperidinecarbonitrile melting at about 202-206C.
~a7973~ :
The nitrile obtained in the preceding paragraph ~
(37.5 parts) was added to 45 5 parts of 75% sulfuric ~ -acid with stirring. The resulting paste was heated to 140-150C. with stirring for 1.5 hours. The mixture was then cooled and 120 parts of anhydrous ethanol was added. The mixture was then distilled unt~l the pot temperature reached 125C. Addition of ethanol and disti-llation was repeated twice before the mixture was finally heated to 150C. and then cooled to room temperature.
It was then poured into ice water containlng~ excess sodium hydroxide. The mixture was then extracted with eth~r and the ether extract was dr:l.e(l an~1 concentrated.
It wa~ then coo:Led to 0C. and r:Lltered to remove solid material. The filtrate was then dlstilled to give a liquid boiling at 120-125C. at 0.1 mm. pressure.
The distillate was then cooled to low temperature (-70C.) whereupon a gummy precipitate formed and the remaining liquid was removed by decantation. The solid was washed with cold pentane and then dried under reduced pre~sure to give crude 4-(LI-chlorophenyl)-4-piperidinecar-boxylic acid ethyl ester.
A solution of 3.3 parts of 3,3,3-triphen~lpro-pionic acid in 108 parts of dry benzene was treated with `~
1.8 parts of thionyl chloride. The mixture was refluxed -for 2 hours before it was cooled and volatile material was removed under reduced pressure. The residue was dissolved in 88 parts of dry benzene and the solvent was removed again under reduced pressure to again give a residual oil. This was again dissoived in 86 parts of ' .
.
~79734 dry benzene and a solution of 2.9 parts Or 4~
chlorophenyl)-4-piperldinecarboxylic acid ethyl ester and 1.1 part of trlethylamine in 27 parts of dry benzene was added at 15-25C. wlth stlrrin~. The mixture was then allowed to stand for 16 hours before it was washed ; successively with dilute hydrochloric acid, water, and dilute aqueous potassium carbonate solution. It was then dried over sodium sulfate and the solvent was evaporated under reduced pressure to leave a residual gum. ~pon trituration with pentane the gum solidified and it was filtered, washed with pentane and air dried to give 1-(3,3,3-trlphenylpropiorly].)~ chlorophenyl)-ll-pLper~ lnecarboxyl:lc acld ethyl ester meltin~ at abou~
95-9~C. 3.~ Parts of this compound was continuously extracted into a suspension of 1.1 part of lithium aluminum hydride in ether with stirring at reflux under nitrogen over a period of one hour. Stirring was continued for an additional 15 minutes and the m:Lxture was decomposed by the successive addition o~ 1.1 part of water, 0.~ part of 20% a~ueous sodium hydroxide solu-tion and 3.9 parts of water. '~he mixture was filtered and the inorganic material was extracted with ether.
The combined ether solutions were concentrated and diluted with pentane. The solid material which formed was separated by filtration, washed with a mixture of ether and pentane, and dried under reduced pressure to give 1-~3,3,3-triphenylpropyl)-4-(4-chlorophenyl)-4-piperi dinemethanol melting at about 156.5-157.5C.
Substitution of p-tolylacetonitrile for L~-, ~ .
107~7341 chlorophenylacetonitrile used above and substantial repetition of the foregoing procedure afforded 1-(3,3,3-triphenylpropyl)-4-~p-tolyl)-4-piperidinemethanol.
A mixture of 10 parts of diphenylmethanol and 11.5 parts of phosphorous pentoxide in 115 parts of thiophene was heated with stirrlng and refluxed under nitrogen for 2 hours. The mixture was cooled and shaken with water but an emulsion formed so that it was further mixed with saturated aqueous sodium chloride solution to break up the emulslon. The th:Lophene layer was ~hen separated and diluted w:lth 210 parts o~' ether and washed ~uccesslvely with water, aqueous 5~ potassium carbonate solution and saturated aqueous sodium chloride solution.
The solution was then dried over sodium sulfate and the solvent evaporated under reduced pressure to leave a residual oil which was first distilled at 300-335C. and then redistilled at 83-90C. at 15 mm. pressure. The resulting material solidified and was recrystallized from ethanol to give 2-thlenyldiphenylmethane melting at about 64-65C. ~
A solution of 1.5 parts of 2-thienyldiphenyl- i ;
methane in 40 parts of cyclohexane was treated with
1-(3,3,3-TRIARYLPROPYL)-4-PI-IENYL-4-PIPERIDINEMETHANOLS
The preient invention relates to compounds of the general formula Ar"
/~\ ~CH20R
Ar'-C-(Alk)-N ~ \ (I) Ar ~
and acid addikion salts thereo~ wherein the Alk ls straight or branched chain alkylene containing 2-l~ carbon atoms; Ar and Ar' are phenyl, alkyl substituted phenyl wherein the alkyl radical contains from 1-4 carbon atoms or halo substituted phenyl; Ar" is phenyl, alkyl sub-stituted phenyl wherein the alkyl radical contains 1-4 lO carbon atoms, halo substituted phenyl, pyridyl or thi.enyl; X i8 hydrogn, halogen or an alkyl radical contalning from 1 to 4 carbon atomEi; R is hydrogenlan alkyl radical containing from 1 to 4 carbon atoms or an alkanoyl radlcal containing from 2-5 carbon atoms. -The alkylene radicals encompassed by the term Alk are exempli~ied by ethylene, propylene, or tri-methylene. The term alkyl radical is exemplified by methyl, ethyl, propyl and butyl. The term alkanoyl . ~ ,' .~
'9734 radical ls exemplified by ethanoyl, propanoyl, butanoyl, and pentanoyl. The term halogen is exempl:Lfied by fluoro, chloro, bromo, or iodo.
The organic bases of this invention form non-toxic acid-addition salts with a variety o:~ organic and inorganic acids. Such salts are formed with acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydri-odic, sulfamic, cltric, lactic, maleic, mallc, succinic~ .
tartaric, cinnamic, acetic, benzoic, gluconic, ascorbic :
and related acids.
The compounds o~ the present lnventlon can be ; :
conveniently prepared by reactin~ a compound o~ the ~cneral formula Ar" -O(Alkyl) Ar'-7~(Alk) ~ . (II) Ar >~ ' ' X/ .:
Il - .
wherein Alk is defined as above or is -Alk'-C-wherein the free valence of the carbonyl is attached to the nitrogen and Alk' is alkylene of 1 to 3 carbon atoms, Alkyl is a radical of 1 to 4 carbon atoms, Ar, Ar', Ar" and X are defined as above with a suitable re-ducing agent in the presence of an organic solvent to 10~973~
give a compound of the general formula Ar"
~ ~C~120 Ar'-C-(Alk)-N
lr ~ (III) X -~ ' wherein Alk, Ar, Ar', Ar" and X are de.~:lned as be~ore wlth the prov:Lso that a) when the compounds of ~ormula I ln whlch R is an alkanoyl radical are desired the .
compounds of formula III are esterified with .
a suitable anhydride in a basic medium to :
give the desired esters of formula I and : .
b) when the compounds of formula I in which R is an alkyl radical are desired.the .
compounds of formula III can be treated with sodium hydride in a sultable solvent and then further treated with an alkyl halide to give the desired ethers of formula I.
Reducing agents suitable for the practice of -this invention are hydrides reducing agents such as lithium aluminum hydride, dissobutylaluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride. A parti-cularly preferred reduing agent is lithium aluminum :
hydride. Organic solvents which are useful for the _L~_ :
. , ,' , ~L079~34 practice of this inventlon are tetrahydrofuran, ethyl ether, 1,2-dimethoxyethane and diglyme (the dimethyl ether of diethylene glycol). Tetrahydrofuran is a preferred . solvent.
An alternate process for the preparation of the compounds of this invention comprises reacting a compound of the formula Ar"
Ar'-C-(Alk)-~
Ar whereln Alk, Ar, Ar', Ar" are defined as before and Z is chlorine or bromine with a compound of the ~eneral for-mula H- ~ ~r~ C~120R
'.
~ .
X '' :-wherein R and X are defined as before in a suitable inert solvent such as toluene, benzene, methylene chloride, 4-methyl-2-pentanone or cyclohexane in the presence of an acid acceptor such as triethylamine or potassium carbo-, . . .
g73~
nate to give the compounds of formula I.
Another process for the preparation ofcompounds of the present invention whereln R of formula I is alkyl or alkanoyl comprises reacting acompound of the general formula Ar"
Ar'-lC-H
Ar where:Ln Ar, Ar~ and Ar" are de~lned as be~ore with n-butyl lithium ln a suitable organic solvent and further re-acting this mixture with a compound of the general formula /--\ / CH20R ' Z-(Alk)-DI~
wherein Alk and X are defined as before and Z is chlorine or bromine and R' is alkyl or alkanoyl to give the compounds of formula I wherein R is alkyl or alkanoyl. :-The compounds of the present invention possess valuable pharmocological properties. They are potent :
anti-diarrheal agents which show little or no analgesia .
107973~
.' ~ !
activity. -Anti-diarrheal utility of the instant compounds is evidenced by their abllity to inhibit gastrointestinal motility as set out in the following tests.
Charcoal Meal Test The method used in the present study has been adapted from techniques previously described (Macht and Barba-Gose, 1931, Janssen and Jageneau, 1957 Sanvordeher and Da~ani, 1975) Male Charles River mice (20-25 g, n=6) prevlously fasted for 2ll hours were ~r~treated with the t;est. compounds aclm:~n:lstered or-ally as a solution ln water or ~uspended :lrl 0.5% rnethyl oellulose.
A constant volume of 10 ml/kg was employed. Thirty minutes following administration of the test compounds, the animals were given a single oral dose of charcoal (0.2 ml per mouse of a 10% charcoal suspended in 1.0%
methyl cellulose). Three and a half hours after char-coal administration, the animals were sacrificed and the cecum examined for the absence or presence of charcoal on an all-or-none basis.
The median effective *ose (ED50) was cal-culated for each compound using the logistic method of Berkson (1953).
.
73~
Castcr Oil Induced Diarrhea in the ~at -Adult Charles River male rats were fasted in community cages for 24 hours prior to the test, with free access to water. The compound was administered intra-gastrically (suspende~ on 0.5% methyl cellulose) onehour prior to the administration of castor oil at the dose of 1.0 ml/rat intragastrically. The rats were then observed for the presence or absence of diarrhea, at hourly intervals for up to 8 hours past administration of castor oll. The median effective dose values at each hourly lnterval was calculated rOr the compound us~ng the me~hod o~ Berk~on (1953). When kestecl .In the above procedures l-(3,3,3-trlphenylpropyl)-l~-phenyl-4-piperi-dinemethanol was found to be very active in its ability to inhibit gastrointestinal motility.
The assessment of the analgesic effect of the instant compounds was conducted in the mouse hot plate and tail clip tests.
Mouse ~lot Plate Test A mouse (adult male weighing 18-25 grams) is placed in a restraining cylinder on a hot plate with the temperature controlled at 55 + 0.3C. The reaction time of the mouse to lick a foot or jump is measured at 60, 40 and 20 minutes before and 30, 60, 90, and 120 minutes after administration of the test compound. The "normal" reaction time is measured as the median of the ;
three pretreatment reaction times. A positive response - , .
consists of a reaction time greater than twice the normal time at any of the post treatment times. A dose Or the test compound is considered active when 50 per cent or more of the animals used show a positive response.
~;
Tail Cli~ Test ; A special clip is applied to the base of the tail of the mouse (adult male weighing 18-25 grams) and the time for the animal to turn around to bite at it is , 10 measured. The sensitivity of each mouse is determined '~ one-half hour prlor to dru~ admin.~stratLon. On:ly tho~e mlce attempt:lng to blte the c.l:lp are lncludecl ln the experiment. The test compound is then administered intraperitoneally and the response to placement of the clip is determined at 30, 60, 90, and 120 minutes after treatment. A response is consldered positive if the , animal takes more than 2 times the pre-drug time to i bite at the clip at any of these time intervals. A
test compound i8 considered active when 50 percent or more of the animals used show a posit:lve response.
when tested in the above procedures l-(3,3,3-triphenyl-propyl)-4-phenyl-4-piperidinemethanol showed very little analgesic effect. .-The following examples describe in detail compounds illustrative of the present invention and methods for their preparation. Throughout the examples hereinafter set forth, temperatures are given in degrees ., Centigrade and relative amounts of materlals in parts _g_ ~C:i 7~734 :
by wei~ht, except as otherwise noted. ~
' EXAMPLE I
- A mixture o~ 2 parts o~ triphenylcarbinol and 8 parts of malonic acid were heated at 170 for 31 hours.
This mixture was cooled and then dissolved in hot ethanol. 3,3,3-Triphenylpropionic acid, melting at 182, crystallized from the ethanol upon cooling. 1 Part of 3,3,3-trlphenylpropionic acid was then refluxed with 5 parts of thionyl chloride for 4 hours and the excess thionyl chloride was removed ln vacuum to provide the crud~ 3,3,3-trlphenylpropionyl chloride. 9 Parts o~
thl~ 3,3,3-trlphenylprop:lonyl chlorlde was then reacted with 27.0 parts o~ ethyl 4-phenyl-4 plperidinecarboxylic acid in the presence of 4 parts of triethylamine in benzene. The resulting amide was reduced with 5 parts of lithium aluminum hydride in ether at reflux ~or 2.5 hours. The reaction mixture was cooled and treated with 15% aqueous sodium hydroxide solution to decompose any unreacted lithium aluminum hydride. The reaction mlxture was then filtered and washed wlth ether. The ether solution was evaporated to give an oil. This oil was then slurried in lO~HCl and partitioned between the ~
acid and ether. The aqueous phase which contained an -~ ~;
insoluble oil was extracted with methylene chloride and dried over anhydrous sodium sulfate. Evaporation of this methylene chloride solution gave a solid which was taken up in acetone and precipitated with ether to give 1 (3,3,3-triphenylpropyl)-4-(4-phenyl)-l~-piperidine-, ~7973~
methanol hydrochloride, melting at about 256-259C.
Substitutlon of 2 parts of (p-chlorophenyl) diphenyl methanol for the triphenylcarbinol used above and substantial repetition of the foregoing procedure afforded 1-[3-(p-chlorophenyl)-3,3-diphenylpropyl~-4-(4-phenyl)-4-piperidinemethanol hydrochloride.
Substitution of 2 parts of l,l-diphenyl-l-(p-tolyl)methanol for the triphenylcarbinol used above and substantial repetition of the procedure of Example I afforded 1-[3-(p-tolyl)-3,3-diphenylpropyl~
phenyl)-l~-piperidlnemethanol hydrochlor:Lde.
F.XAMPLE 2 A mixture of 18.9 parts of ethyl ~I-phenyl-L~-piperidinecarboxylic acid, 81.1 parts of 4-methyl-2-pentanone, 7.2 parts of ethylene oxide and 40 parts ofmethanol was heated in a citric bottle at about 65C.
~or 3 days. The resulting solution was cooled, the solvent was evaporated under reduced pressure and the resldual material was partitioned between water and methylene chloride. The methylene chloride layer was then separated and dried and the solvent evaporated under reduced pressure. The resulting residue was then par-titioned between dilute hydrochloric acid and ether.
The acid layer was then made alkaline with aqueous sodium hydroxide and the resultlng mixture was extracted with ether. The ether was dried over sodium sulfate and potassium carbonate and concentrated before it was ~inally diluted with pentane. The precipitate which , 1~7973~ ~
formed was separated by filtration, washed and then dried and then finally recrystallized from hexane to give 1-(2-hydroxyethyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester melting at about 82-85C.
A solution was prepared from 9.1 parts of the ester obtained in the preceding paragraph and 330 parts of methylene chloride. This solution was saturated with hydrogen chloride gas at ice bath temperature and ~ parts of thionyl chloride was added. The mixture was re-fluxed for 75 minutes and then cooled and volatile materlal was removed under reduced pressure. The result-lng resiclual sol:ld was washed w-Lth benzene, dr:Le~ ln air ancl then recryst~ d ~rom a m:Lxture Or ethanol ~nd ether to give 1-(2-chloroethyl)-4-phenyl-4-piperidine-carboxylic acid ethyl ester hydrochloride melting atabout 208-213C. To a solution of 3.l~ parts of diphenyl-2-pyridylmethane in 100 parts of cyclohexane was added, at 10-15C. under nitrogen, 8 parts by volume of a 2 molar solution of butyllithium in hexane.
This solution was stlrred at room temperature ~or 30 minutes and th~n a solution of ethyl 1-(2-chloroethyl)-4-phenyl-ll-piperidinecarboxylate, obtained from 4 7 parts of the corresponding hydrochloric salts, in 24 parts of `
cyclohexane was added and the mixture was refluxed with stirring for 3 hours. The resulting solution was cooled, diluted with 105 parts of ether and then washed with aqueous sodium hydroxide solution. The organic solu-tion was then dried and the solvent evaporated under reduced pressure to leave a residual red-brown gum which 1~7973~
solidified. This was washed with pentane and then air dried to give crude ethyl l-[3,3-diphenDl-3-(2-pyridyl)propyl]-4-phenyl-4-piperidinecarboxylate. A
mixture of 3.ll parts of this crude ester and o.8~ part of lithium aluminum hydride in 87 parts of ether was heated and stirred under nitrogen ror 1.3 hours. The mixture was then decomposed by the successive addition of 0.9 part of water, 0.7 part of aqueous sodium hydroxide solu-tion, and 3.2 parts of water. The mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure. The residual material was washed with pentane and then dissolved in 250 parts of boiling ebher-. ~his was concentrated to a smallv~ume and cooled and ~he solid which rormed was separated by E`lltratlon and recrystalli~ed twice ~rom ether to ~,ive 1-[3,3-diphenyl-3-(2-pyridyl)propyl]-4-phenyl-4-piperidinemethanol melting at about 148-15QC.
A mixture of 1 part of 1-(3,3,3-triphenyl-propyl)-4-phenyl-ll-piperidinemethanol hydrochloride, 10 parts of pyridine and 3.2 parts of acetic anhydrlde was allowed to stand for 24 hours. Volatile material was removed under reduced pressure and the resulting residue was partitioned between dilute sodium hydroxide and ether. The ether layer was separated, washed with water, dried over sodium sulfate and then treated with an excess of a solution of hydrogen chloride in 2-propanol.
The solid which formed was separated by filtration and : , . .
79'73~
then washed successively with ether, water, and ether, and then air dried to give l-(3,3,3-triphenylpropyl)-4-phenyl-4-acetoxymethylpiperidine hydrochloride melting at about 210-213C.
, EXAMpLE ll A solution of 3 parts of 1-(3,3,3-triphenyl-propyl)-4-phenyl-4-piperidinemethanol (obtained from the corresponding hydrochlorlde salt), 0.35 parts of sodium hydride as a 50% suspension in mineral oil, and 70 parts by volume of 1,2-dimethoxyethane were heated at 37-39C. ~or 1.5 hours under nitrogen wlth st:l.rrlrl~.
The rnlxture was cooled to room temper-a~ure and ~.9 part of' methyl iodide was added and the mixture was stirred at room temperature for 20 hours. The solvent was eva-porated under reduced pressure and the residue was tri-turated with ether. The resulting solid was then separated by filtration, dissolved in ether and treated with an excess of hydrogen chloride in 2-propanol.
The solid which formed was separated by filtration, washed wlth ether, and alr dr:led and then f`urther recrystallized from a mixture of methanol and ether to give 1-~3,3,3-tri-phenylpropyl)-4-phenyl-4-methoxymethylpiperidine hydro-chloride melting at about 212-213.5C.
.
:
.
~07973~L
EX~MPL~ 5 A mixture of 63.7 parts Or bls-2-chloroethyl-amine hydrochloride, 67.~ parts of 4-toluenesulphonyl chloride and 955 parts of methylene chloride was cooled in an ice bath and then 356 parts by volume of a 2 N
aqueous sodium hydroxide solution was added with stirring at 5~~C. The mixture was stirred at 5-8C.
for 3 hours and then at room temperature for 18 hours.
The organic layer was separated and washed successively with dilute hydrochloric acid, water, dilute potassium carbonate solution, and water and then dried over sodlum ~,ulfate. The solvent was then evapora~ed under reduced pressure and the rosldual o:Ll was crystalll~.ed from methanol to ~ive N,N-bis(2-chloroethyl)~ll-toluene-sulfonamide melting at about 45-ll7C.
To a solution of 60 parts of 4-chlorophenylaceto-nitrile and ll~ parts of N,N-bis(2-chloroethyl)-4-toluenesulfonamide in 720 parts of dried benzene, there was added portionwise with stirring at 10-13C., 32.6 parts of sodamide. The cooling bath was then removed and the mlxture was stirred ~or one hour during which tlme the temperature rose to 70C. and then fell back to 43C-Ice cold water was added to the mixture and a fine solid formed. This was separated by filtration and washed successively with water and benzene and dried and then triturated in boiling methanol. The undissolved solid was separated by filtration, washed with water and dried to give 1-(4-toluenesulfonyl)-4-(4-chlorophenyl)-4-piperidinecarbonitrile melting at about 202-206C.
~a7973~ :
The nitrile obtained in the preceding paragraph ~
(37.5 parts) was added to 45 5 parts of 75% sulfuric ~ -acid with stirring. The resulting paste was heated to 140-150C. with stirring for 1.5 hours. The mixture was then cooled and 120 parts of anhydrous ethanol was added. The mixture was then distilled unt~l the pot temperature reached 125C. Addition of ethanol and disti-llation was repeated twice before the mixture was finally heated to 150C. and then cooled to room temperature.
It was then poured into ice water containlng~ excess sodium hydroxide. The mixture was then extracted with eth~r and the ether extract was dr:l.e(l an~1 concentrated.
It wa~ then coo:Led to 0C. and r:Lltered to remove solid material. The filtrate was then dlstilled to give a liquid boiling at 120-125C. at 0.1 mm. pressure.
The distillate was then cooled to low temperature (-70C.) whereupon a gummy precipitate formed and the remaining liquid was removed by decantation. The solid was washed with cold pentane and then dried under reduced pre~sure to give crude 4-(LI-chlorophenyl)-4-piperidinecar-boxylic acid ethyl ester.
A solution of 3.3 parts of 3,3,3-triphen~lpro-pionic acid in 108 parts of dry benzene was treated with `~
1.8 parts of thionyl chloride. The mixture was refluxed -for 2 hours before it was cooled and volatile material was removed under reduced pressure. The residue was dissolved in 88 parts of dry benzene and the solvent was removed again under reduced pressure to again give a residual oil. This was again dissoived in 86 parts of ' .
.
~79734 dry benzene and a solution of 2.9 parts Or 4~
chlorophenyl)-4-piperldinecarboxylic acid ethyl ester and 1.1 part of trlethylamine in 27 parts of dry benzene was added at 15-25C. wlth stlrrin~. The mixture was then allowed to stand for 16 hours before it was washed ; successively with dilute hydrochloric acid, water, and dilute aqueous potassium carbonate solution. It was then dried over sodium sulfate and the solvent was evaporated under reduced pressure to leave a residual gum. ~pon trituration with pentane the gum solidified and it was filtered, washed with pentane and air dried to give 1-(3,3,3-trlphenylpropiorly].)~ chlorophenyl)-ll-pLper~ lnecarboxyl:lc acld ethyl ester meltin~ at abou~
95-9~C. 3.~ Parts of this compound was continuously extracted into a suspension of 1.1 part of lithium aluminum hydride in ether with stirring at reflux under nitrogen over a period of one hour. Stirring was continued for an additional 15 minutes and the m:Lxture was decomposed by the successive addition o~ 1.1 part of water, 0.~ part of 20% a~ueous sodium hydroxide solu-tion and 3.9 parts of water. '~he mixture was filtered and the inorganic material was extracted with ether.
The combined ether solutions were concentrated and diluted with pentane. The solid material which formed was separated by filtration, washed with a mixture of ether and pentane, and dried under reduced pressure to give 1-~3,3,3-triphenylpropyl)-4-(4-chlorophenyl)-4-piperi dinemethanol melting at about 156.5-157.5C.
Substitution of p-tolylacetonitrile for L~-, ~ .
107~7341 chlorophenylacetonitrile used above and substantial repetition of the foregoing procedure afforded 1-(3,3,3-triphenylpropyl)-4-~p-tolyl)-4-piperidinemethanol.
A mixture of 10 parts of diphenylmethanol and 11.5 parts of phosphorous pentoxide in 115 parts of thiophene was heated with stirrlng and refluxed under nitrogen for 2 hours. The mixture was cooled and shaken with water but an emulsion formed so that it was further mixed with saturated aqueous sodium chloride solution to break up the emulslon. The th:Lophene layer was ~hen separated and diluted w:lth 210 parts o~' ether and washed ~uccesslvely with water, aqueous 5~ potassium carbonate solution and saturated aqueous sodium chloride solution.
The solution was then dried over sodium sulfate and the solvent evaporated under reduced pressure to leave a residual oil which was first distilled at 300-335C. and then redistilled at 83-90C. at 15 mm. pressure. The resulting material solidified and was recrystallized from ethanol to give 2-thlenyldiphenylmethane melting at about 64-65C. ~
A solution of 1.5 parts of 2-thienyldiphenyl- i ;
methane in 40 parts of cyclohexane was treated with
2.5 parts by volume of a 2.5 molar solution of butyl-lithium in hexane. Then 0.67 part of potassium t-butoxide was added and an immediate red color appeared. The mixture was stirred for 1 hour and then 1-(2-chloroethyl)-4-phenyl-4-methoxymethylpiperidine in 12 parts of cyclo-7973~
hexane was added. The mixture was refluxed for 2 hoursand then cooled and diluted with 70 parts of ether. The organic layer was then washed with water and extracted with dilute hydrochloric acid. The aqueous layer was combined with the brown gum that formed and made strongly alkaline with aqueous sodium hydroxide solution. This alkaline solution was extracted with ether and the ether extract was dried over sodium sulfate and treated with an excess of hydrogen chloride in 2 propanol. The pre-cipitate which formed was separated and dissolved in waterand the aqueous solutlon was nlade alkaline wL~ih a(lueous ~odium hydroxide solut:Lon. This ~olut:lon was therl ex-tracted wlth ether and drled and the solvent wa~ eva-porated under reduced pressure to leave a light brown ]5 gum which was chromatographed on a silica gel column.
Appropriate fractions were combined and the solvent evaporated to leave a residual oil which was dissolved in ethanol and mixed with oxalic acid. The precipitate which formed was separated by filtration and recrystallized ~rom a m.ixture of methanol ancl ether to give 1-[3-~2~
thienyl)-3,3-diphenylpropyl]-~ l-phen;Yl)-ll-methoxymethyl~
plperidine oxalate.
EXA~PLE 7 -4,4,4-Triphenylbutyronitrile was hydrolized by standard procedure to give 4,ll,4-triphenylbutyric acid.
; Substitution of 4,4,4-triphenylbutyric acid for the
hexane was added. The mixture was refluxed for 2 hoursand then cooled and diluted with 70 parts of ether. The organic layer was then washed with water and extracted with dilute hydrochloric acid. The aqueous layer was combined with the brown gum that formed and made strongly alkaline with aqueous sodium hydroxide solution. This alkaline solution was extracted with ether and the ether extract was dried over sodium sulfate and treated with an excess of hydrogen chloride in 2 propanol. The pre-cipitate which formed was separated and dissolved in waterand the aqueous solutlon was nlade alkaline wL~ih a(lueous ~odium hydroxide solut:Lon. This ~olut:lon was therl ex-tracted wlth ether and drled and the solvent wa~ eva-porated under reduced pressure to leave a light brown ]5 gum which was chromatographed on a silica gel column.
Appropriate fractions were combined and the solvent evaporated to leave a residual oil which was dissolved in ethanol and mixed with oxalic acid. The precipitate which formed was separated by filtration and recrystallized ~rom a m.ixture of methanol ancl ether to give 1-[3-~2~
thienyl)-3,3-diphenylpropyl]-~ l-phen;Yl)-ll-methoxymethyl~
plperidine oxalate.
EXA~PLE 7 -4,4,4-Triphenylbutyronitrile was hydrolized by standard procedure to give 4,ll,4-triphenylbutyric acid.
; Substitution of 4,4,4-triphenylbutyric acid for the
3,3,3-triphenylpropionic acid of Example 1 and sub-stantial repetition of the procedure of Example I afforded .
lV797~3~
1-(4,4,4-triphenylbutyl)-ll-(4-phenyl)-ll-piperidinemethanol.
' EXAMPLI ~
A mixture of 1.-7 parts of 3,3,3-triphenylpropyl-chloride, 0.49 part of 4-phenyl-ll-piperldinemethanol hydrochloride, o.46 part Or potassiu~ carbonate, 0.17 part of potassium iodide, 1 part Or ~1ater and 3.2 parts of 4-methyl-2-pentanone was refluxed for 2 hours. The solvent was then evaporated and the residue was parti-tioned between methylene chloride and water. The organic layer was separated, washed w:l.th water and with aaturated a~ueous sodlulll chlorlcle so:l.utlon ancl ~hen dr:Led over sod:lum sulrate. ~i,vaporatlorl of the solven~
left a semi-solid residue wh:lch was slurried in ether and then filtered to remove the solid. The solvent was evaporated from the filtrate leaving an oily residue which was taken up in refluxing hexane. The hexane solution was then decanted and cooled and the oily solid which formed was removed by filtration. Evaporation o~ the solvent ~rom the filtra~e gave 1-(3,3,3-triphenylpropyl)~
(ll-phenyl)-4-plperldinemethanol.
.;
Pharmaceutical formulations were prepared in the following manner with amounts indicating the relative amounts per 1000 tablets, capsules, suppositories or parenteral products.
Tablets 2.5 grams of a representative compound, e.g.
1~79734 1-(3,3,3-triphenylpropyl)-4-(4-phenyl)-LI-p:iperidinen}ethanol hydrochloride were dissolved in isopropyl alcohol and dis-tributed on 380 grams of lactose. The m:ixture was air-dried and passed through a 40 mesh screen. lO0 grarns of corn starch and 15 grams of polyvinylpyrro:Lidone were added to the drug substance lactose mixture, mixed thoroughly and passed through a 40 mesh screen. The mixture was then granulated with isopropyl alcohol, spread on trays, and dried at 120F. for 16 hours. The dried granulation was then screened. The granules were mixed thoroughly with 2.5 grams of magneslum stearate and the mixture compressed into tablets o~ the approprlate slze.
'rhere was thus obtalned ~ batch Oe looo t,ablets havLn~ a concentration of actlve lngredlent of 2.5 mg/tablet.
Capsules 2.5 grams of 1-(3,3,3-trlphenylpropyl)_4_ (4-phenyl)-4-piperidinemethanol hydrochloride were mixed thoroughly with 95 7sgrams of corn starch and 95.75 grams of lactose, screened through a ~lO mesh screen, and remlxed. 6.0 gram~ o~ talc were added and the m:Lxture was thoroughly mixed and fllled lnto the approprlate hard gelatin capsule by hand or machine using 200 mg.
fill per capsule. There was thus obtained a batch of 1000 capsules having a concentration of active ingre-dients of 2.5 mg.capsule.
In the preparation of tablets and capsules fromthe compounds of the present invention, a variety of excipients can be used. These are sum~arized as follows:
. .
~C1797~A
Sugars such as lactose, sucrose, mannitol, or sorb-ltol;
starches such as corn starch, tapioca starchJor potatostarch;
cellulose derlvatives such as sodlum carboxymethyl cellu-lose, ethyl cellulose, or methyl cellulose; gelatin; cal-cium phosphates such as dicalcium phosphate or tricalciumphosphate; sodium sulfate; calcium sulfate; polyvinyl-pyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate; stearic acid vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil; surfactants (nonionic, cationic, anionic); ethylene glycol polymers; beta-cyclo-dextrin; fatty alcohols; hyclrolyzed cerea:L solids; as w~ll as other non-tox:Lc compat:l.bl~ ~:I.llers, b:Lnde:rl3, dis-inte~,rant~, and lubr~cants commonly USQd ln pharmnoeutlcal rormula~ions.
Parenteral Products 0.5 gram of 1-(3,3,3-triphenylpropyl)-4-(4-phenyl)-4-piperidinemethanol hydrochloride was :
dissolved in 0.5 liter of ethanol and 5.0 liters of sesame oil, filtered and filled into ampuls and sealed. The ~ :
ampuls were then sterilized by an approprlate procedure.
There was thus obtained a batch of 1000 ampuls having a concentration of active ingredient 0.5 mg/5ml. .: ;
In the preparation of parenteral products ~rom the compounds of the present invention a variety of :
vehicles and solubilizers can be used. These are summar-ized as follows: Vegetable oils such as peanut, corn, cottonseed, sesame oil, benzyl alcohol, saline, phos-.
;.
' phate buffer, water, ethylene glycol polymers, urea, dimethylacetamide, triton, dioxolanes, ethyl carbonate, ethyl lactate, glycerol formal, isopropyl myristate, sur-factants (nonlonic, cationic, anionic), polyalcohols, ethanol.
Suppositories 240.0 grams of cocoa butter were melted, pre-ferably on a water or stea~ bath to avoid local over-heating, then 10.0 grams of 1-(3,3,3-triphenylpropyl)-
lV797~3~
1-(4,4,4-triphenylbutyl)-ll-(4-phenyl)-ll-piperidinemethanol.
' EXAMPLI ~
A mixture of 1.-7 parts of 3,3,3-triphenylpropyl-chloride, 0.49 part of 4-phenyl-ll-piperldinemethanol hydrochloride, o.46 part Or potassiu~ carbonate, 0.17 part of potassium iodide, 1 part Or ~1ater and 3.2 parts of 4-methyl-2-pentanone was refluxed for 2 hours. The solvent was then evaporated and the residue was parti-tioned between methylene chloride and water. The organic layer was separated, washed w:l.th water and with aaturated a~ueous sodlulll chlorlcle so:l.utlon ancl ~hen dr:Led over sod:lum sulrate. ~i,vaporatlorl of the solven~
left a semi-solid residue wh:lch was slurried in ether and then filtered to remove the solid. The solvent was evaporated from the filtrate leaving an oily residue which was taken up in refluxing hexane. The hexane solution was then decanted and cooled and the oily solid which formed was removed by filtration. Evaporation o~ the solvent ~rom the filtra~e gave 1-(3,3,3-triphenylpropyl)~
(ll-phenyl)-4-plperldinemethanol.
.;
Pharmaceutical formulations were prepared in the following manner with amounts indicating the relative amounts per 1000 tablets, capsules, suppositories or parenteral products.
Tablets 2.5 grams of a representative compound, e.g.
1~79734 1-(3,3,3-triphenylpropyl)-4-(4-phenyl)-LI-p:iperidinen}ethanol hydrochloride were dissolved in isopropyl alcohol and dis-tributed on 380 grams of lactose. The m:ixture was air-dried and passed through a 40 mesh screen. lO0 grarns of corn starch and 15 grams of polyvinylpyrro:Lidone were added to the drug substance lactose mixture, mixed thoroughly and passed through a 40 mesh screen. The mixture was then granulated with isopropyl alcohol, spread on trays, and dried at 120F. for 16 hours. The dried granulation was then screened. The granules were mixed thoroughly with 2.5 grams of magneslum stearate and the mixture compressed into tablets o~ the approprlate slze.
'rhere was thus obtalned ~ batch Oe looo t,ablets havLn~ a concentration of actlve lngredlent of 2.5 mg/tablet.
Capsules 2.5 grams of 1-(3,3,3-trlphenylpropyl)_4_ (4-phenyl)-4-piperidinemethanol hydrochloride were mixed thoroughly with 95 7sgrams of corn starch and 95.75 grams of lactose, screened through a ~lO mesh screen, and remlxed. 6.0 gram~ o~ talc were added and the m:Lxture was thoroughly mixed and fllled lnto the approprlate hard gelatin capsule by hand or machine using 200 mg.
fill per capsule. There was thus obtained a batch of 1000 capsules having a concentration of active ingre-dients of 2.5 mg.capsule.
In the preparation of tablets and capsules fromthe compounds of the present invention, a variety of excipients can be used. These are sum~arized as follows:
. .
~C1797~A
Sugars such as lactose, sucrose, mannitol, or sorb-ltol;
starches such as corn starch, tapioca starchJor potatostarch;
cellulose derlvatives such as sodlum carboxymethyl cellu-lose, ethyl cellulose, or methyl cellulose; gelatin; cal-cium phosphates such as dicalcium phosphate or tricalciumphosphate; sodium sulfate; calcium sulfate; polyvinyl-pyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate; stearic acid vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil; surfactants (nonionic, cationic, anionic); ethylene glycol polymers; beta-cyclo-dextrin; fatty alcohols; hyclrolyzed cerea:L solids; as w~ll as other non-tox:Lc compat:l.bl~ ~:I.llers, b:Lnde:rl3, dis-inte~,rant~, and lubr~cants commonly USQd ln pharmnoeutlcal rormula~ions.
Parenteral Products 0.5 gram of 1-(3,3,3-triphenylpropyl)-4-(4-phenyl)-4-piperidinemethanol hydrochloride was :
dissolved in 0.5 liter of ethanol and 5.0 liters of sesame oil, filtered and filled into ampuls and sealed. The ~ :
ampuls were then sterilized by an approprlate procedure.
There was thus obtained a batch of 1000 ampuls having a concentration of active ingredient 0.5 mg/5ml. .: ;
In the preparation of parenteral products ~rom the compounds of the present invention a variety of :
vehicles and solubilizers can be used. These are summar-ized as follows: Vegetable oils such as peanut, corn, cottonseed, sesame oil, benzyl alcohol, saline, phos-.
;.
' phate buffer, water, ethylene glycol polymers, urea, dimethylacetamide, triton, dioxolanes, ethyl carbonate, ethyl lactate, glycerol formal, isopropyl myristate, sur-factants (nonlonic, cationic, anionic), polyalcohols, ethanol.
Suppositories 240.0 grams of cocoa butter were melted, pre-ferably on a water or stea~ bath to avoid local over-heating, then 10.0 grams of 1-(3,3,3-triphenylpropyl)-
4-(4-phenyl)-4-piperidinemethanol hydrochloride was either emulsified or suspended in the melt. ~inally, the mass wa~ poured into cooled metal molds, wh~ch were chrome plated and the supposlkory was readlly solldi~lecl. The total welght of the supposltory was 250.0 mg.
In the preparation of suppositories from the compounds of the present invention a variety of vehicles and bases for suppository application can be used. These are summarized as follows: Triglycerides of oleic, palmitric, and stearic acids (cocoa butter), partially hydrogenated cotton~eed oil, branched saturated fatty alcohols such as Suppository base G, Elydrogenated coconut oil triglycerides of C12-C18 fatty acids, water disper-sible vehicles such as the polyethylene glycols, glycerin, gelatin, polyoxyl 40 stearates, and polyethylene-4-sorbi-tan monostearates, and materials which can raise themelting point of the suppository base, such as beeswax, spermaceti, etc.
1~97~
SUPPLEMENTARY DISCLOSURE
The foregoing disclosure describes certain compounds~
defined by general formula (I), and acid addition salts thereof, wherein the radical R is defined as hydrogen, an alkyl radical containing from 1 to 4 carbon atoms or an alkanoyl radical containing from 2 to 5 carbon atoms.
We have now found that certain related compounds of general formula (I) wherein the radical R is an alkyl radical containing from 5 to 10 carbon atoms likewise possess valuable pharmacological properites and are potent anti-diarrheal agents.
The present invention further relates to compounds of the general formula Ar"
~ CH20R
Ar'-C-(Alk)-N ~
Ar ~ (I) or an acid addition salt thereof wherein the Alk is straight or branched chain alkylene containing 2-4 carbon atoms; Ar and Ar' are phenyl, Ar" is phenyl or pyridyl; X is hydrogen, halogen or methyl; and R is an alkyl radical containing ~rom
In the preparation of suppositories from the compounds of the present invention a variety of vehicles and bases for suppository application can be used. These are summarized as follows: Triglycerides of oleic, palmitric, and stearic acids (cocoa butter), partially hydrogenated cotton~eed oil, branched saturated fatty alcohols such as Suppository base G, Elydrogenated coconut oil triglycerides of C12-C18 fatty acids, water disper-sible vehicles such as the polyethylene glycols, glycerin, gelatin, polyoxyl 40 stearates, and polyethylene-4-sorbi-tan monostearates, and materials which can raise themelting point of the suppository base, such as beeswax, spermaceti, etc.
1~97~
SUPPLEMENTARY DISCLOSURE
The foregoing disclosure describes certain compounds~
defined by general formula (I), and acid addition salts thereof, wherein the radical R is defined as hydrogen, an alkyl radical containing from 1 to 4 carbon atoms or an alkanoyl radical containing from 2 to 5 carbon atoms.
We have now found that certain related compounds of general formula (I) wherein the radical R is an alkyl radical containing from 5 to 10 carbon atoms likewise possess valuable pharmacological properites and are potent anti-diarrheal agents.
The present invention further relates to compounds of the general formula Ar"
~ CH20R
Ar'-C-(Alk)-N ~
Ar ~ (I) or an acid addition salt thereof wherein the Alk is straight or branched chain alkylene containing 2-4 carbon atoms; Ar and Ar' are phenyl, Ar" is phenyl or pyridyl; X is hydrogen, halogen or methyl; and R is an alkyl radical containing ~rom
5 to 10 c~rbon atoms.
The term alkyl radical is exempli~ied by pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
The compounds of the present invention can be .
conveniently prepared by reacting a compound of the general formula Ar"
/~ CH2H
Ar'-7- (Alk)-N
Ar /~ ,' ~' X
-2~-~C~79'734 wherein Alk, Ar, Ar', Ar" and X are defined as before with sodium hydride in a suitable solvent to g.ive a compound of khe formula Ar"
/--\ ~CH 2 0Na Ar'-C-(Alk)-N~
Ar ,~
X
wherein Alk, Ar, Ar', Ar" and X are defined and then further treating this compound with an alkyl halide wherein the alkyl moiety contains 5 to 10 carbon atoms to give compounds of formula I.
Organic solvents which are useful for the practice oE
this invention are tetrahydrofuran, ethyl ether, 1,2-dimethoxy-ethane and diglyme (the dimethyl ether of diethylene glycol).
1,2-Dimethoxyethane is a preferred solvent.
An alternate process for the preparation of the . .
compounds comprises reacting a compound of the formula Ar"
Ar'-j-(Alk)-Z ..
Ar -wherein Alk, Ar, Ar', Ar" are defined as before and g is chlorine or bromine with a compound of the general formula CH20R '~ "
H-N~
~ ~ -25-.. . . , .,,~ ,. . , .. ~
. .
~ 973~ :
wherein R and X are defined as before in a suitable inert solven-t such as toluene, benzene, methylene chloride, 4- ;
methyl-2-pentanone or cyclohexane in the presence of an acid s acceptor such as triethylamine or potassium carbonate to give the compounds of formula I.
Anti-diarrheal utility of the compounds is evidenced by their ability to inhibit gastrointestinal motility as set out in the following tests.
In the foregoing charcoal meal test, the median effective dose (ED50) for the compound, 1-(3,3,3-triphenyl-propyl)-4-phenyl-4-hexyloxy-methylpiperidine, was 4.04 + 1.66 mg/kg IG.
In the castor oil induced diarrhea test, the compound 1-~3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine, had an ED50 of 0.76 ~ 0.12 mg/kg IG at the 2nd hour. ~ ;
The following additional examples describe in detail -compounds illustrative of the present invention and methods for their preparation. The relationship between parts by weight and parts by volume is the same as that existing between grams and milliliters.
A suspension o 2.84 parts by weight of 1-(3,3,3-triphenylpropyl)-4-phenyl-4 piperdine methanol (obtained ~rom the corresponding hydrochloride), 0.34 parts by weight of a 50% sodium hydride suspension in mineral oil and 70 parts by -volume of 1,2-dimethoxyethane were heated at 40C. for 2.0 hours under nitrogen with stirring. The mixture was cooled to room temperature and 0.87 parts by volume of n-hexylbomide was added and then the mixture was stirred at room temperature for five days. The solvent was evaporated under reduced pressure to give a gum which was treated with ether. The undissolved solid was filtered off. The filtrate was then stripped in vacuo ; ~ -26-973~
to leave a residue. The residue was partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride layer was then washed with water, clried over sodium sulfate and stripped in vacuo to afford a gum. This yum was chromatographed on neutral silica gel using a solvent mixture of ethanol-benzene (2:98) as the eluent. The desired fractions were combined and evaporated. The resulting residue was chromatographed again using neutral silica qel as the column adsorbent and a solvent mixture of benzene-ethanol-concentrated ammonium hydroxide (85:14:1) as the eluent under low pressure.
The desired fractions from the chromatography are combined and stripped ln vacuo to leave an oil. The oil was then dissolved in ether and filtered. The filtrate was teated with excess 7N
hydrochloric acid/isopropanol solution and stripped in vacuo to aEford a gum. Treatment of the gum with ether resulted in the solidification o~ the gum. This mixture was stripped ln vacuo to afford a white residual solid. This solid was recrystallized from acetone-ether and dried in vacuo to give 1-(3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine hydrochloride, melting at 152-155C.
Substitution of octyl bromide Eor the hexyl bromide used `~
above and substantial repetition of the procedure afforded 1-(3,3,3-triphenylpropyl)-4-phenyl-4-octyloxymethylpiperidine hydrochloride.
Substitution of 1-(3,3,3-triphenylpropyl)-4-(4-chloro-phenyl)-4-piperidinemethanol for the 1-(3,3,3-triphenylpropyl)-4-phenyl-4-piperidinemethanol used above and substantial repetition of the procedure afforded 1-~3,3,3-triphenylpropyl)-4-(4-chlorophenyl)-4-hexyloxymethylpiperidine hydrochloride.
Pharmaceutical formulationswere prepared in the following manner with amounts indicating the relative amounts per 1000 ~ ~ -27-lV~73~
tablets, capsules, suppositories or parenteral products.
Tablets 2.5 Grams of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine hydrochloride were formulated into tablets according to the procedure described in Example 9.
There wa~ thus obtained a batch of 1000 tablets having a concentration of active ingredient of 2.5 mg/tablet.
Capsules . ' ~., 2.5 Grams of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-. . ~ ,. . .
hexyloxymethylpiperidine hydrochloride were formulated into capsules according to the procedure described in Example 9.
There was thus obtained a batch o 1000 capsules having a concentration of active ingredients oE 2.5 mg. capsule.
Parenteral Products 0.5 Gram of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine hydrochloride was formulated into ;
ampuls according to the procedure described in Example 9.
There was thus obtained a batch of 1000 ampuls having a concentration of active ingredient 0.5 mg/5ml.
Suppositories 10.0 Grams o 1-(3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine hydrochloride were ormulated into ~
suppositories according to the procedure described in Example 9. .
The total weight of each suppository was 250.0 mg.
The term alkyl radical is exempli~ied by pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
The compounds of the present invention can be .
conveniently prepared by reacting a compound of the general formula Ar"
/~ CH2H
Ar'-7- (Alk)-N
Ar /~ ,' ~' X
-2~-~C~79'734 wherein Alk, Ar, Ar', Ar" and X are defined as before with sodium hydride in a suitable solvent to g.ive a compound of khe formula Ar"
/--\ ~CH 2 0Na Ar'-C-(Alk)-N~
Ar ,~
X
wherein Alk, Ar, Ar', Ar" and X are defined and then further treating this compound with an alkyl halide wherein the alkyl moiety contains 5 to 10 carbon atoms to give compounds of formula I.
Organic solvents which are useful for the practice oE
this invention are tetrahydrofuran, ethyl ether, 1,2-dimethoxy-ethane and diglyme (the dimethyl ether of diethylene glycol).
1,2-Dimethoxyethane is a preferred solvent.
An alternate process for the preparation of the . .
compounds comprises reacting a compound of the formula Ar"
Ar'-j-(Alk)-Z ..
Ar -wherein Alk, Ar, Ar', Ar" are defined as before and g is chlorine or bromine with a compound of the general formula CH20R '~ "
H-N~
~ ~ -25-.. . . , .,,~ ,. . , .. ~
. .
~ 973~ :
wherein R and X are defined as before in a suitable inert solven-t such as toluene, benzene, methylene chloride, 4- ;
methyl-2-pentanone or cyclohexane in the presence of an acid s acceptor such as triethylamine or potassium carbonate to give the compounds of formula I.
Anti-diarrheal utility of the compounds is evidenced by their ability to inhibit gastrointestinal motility as set out in the following tests.
In the foregoing charcoal meal test, the median effective dose (ED50) for the compound, 1-(3,3,3-triphenyl-propyl)-4-phenyl-4-hexyloxy-methylpiperidine, was 4.04 + 1.66 mg/kg IG.
In the castor oil induced diarrhea test, the compound 1-~3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine, had an ED50 of 0.76 ~ 0.12 mg/kg IG at the 2nd hour. ~ ;
The following additional examples describe in detail -compounds illustrative of the present invention and methods for their preparation. The relationship between parts by weight and parts by volume is the same as that existing between grams and milliliters.
A suspension o 2.84 parts by weight of 1-(3,3,3-triphenylpropyl)-4-phenyl-4 piperdine methanol (obtained ~rom the corresponding hydrochloride), 0.34 parts by weight of a 50% sodium hydride suspension in mineral oil and 70 parts by -volume of 1,2-dimethoxyethane were heated at 40C. for 2.0 hours under nitrogen with stirring. The mixture was cooled to room temperature and 0.87 parts by volume of n-hexylbomide was added and then the mixture was stirred at room temperature for five days. The solvent was evaporated under reduced pressure to give a gum which was treated with ether. The undissolved solid was filtered off. The filtrate was then stripped in vacuo ; ~ -26-973~
to leave a residue. The residue was partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride layer was then washed with water, clried over sodium sulfate and stripped in vacuo to afford a gum. This yum was chromatographed on neutral silica gel using a solvent mixture of ethanol-benzene (2:98) as the eluent. The desired fractions were combined and evaporated. The resulting residue was chromatographed again using neutral silica qel as the column adsorbent and a solvent mixture of benzene-ethanol-concentrated ammonium hydroxide (85:14:1) as the eluent under low pressure.
The desired fractions from the chromatography are combined and stripped ln vacuo to leave an oil. The oil was then dissolved in ether and filtered. The filtrate was teated with excess 7N
hydrochloric acid/isopropanol solution and stripped in vacuo to aEford a gum. Treatment of the gum with ether resulted in the solidification o~ the gum. This mixture was stripped ln vacuo to afford a white residual solid. This solid was recrystallized from acetone-ether and dried in vacuo to give 1-(3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine hydrochloride, melting at 152-155C.
Substitution of octyl bromide Eor the hexyl bromide used `~
above and substantial repetition of the procedure afforded 1-(3,3,3-triphenylpropyl)-4-phenyl-4-octyloxymethylpiperidine hydrochloride.
Substitution of 1-(3,3,3-triphenylpropyl)-4-(4-chloro-phenyl)-4-piperidinemethanol for the 1-(3,3,3-triphenylpropyl)-4-phenyl-4-piperidinemethanol used above and substantial repetition of the procedure afforded 1-~3,3,3-triphenylpropyl)-4-(4-chlorophenyl)-4-hexyloxymethylpiperidine hydrochloride.
Pharmaceutical formulationswere prepared in the following manner with amounts indicating the relative amounts per 1000 ~ ~ -27-lV~73~
tablets, capsules, suppositories or parenteral products.
Tablets 2.5 Grams of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine hydrochloride were formulated into tablets according to the procedure described in Example 9.
There wa~ thus obtained a batch of 1000 tablets having a concentration of active ingredient of 2.5 mg/tablet.
Capsules . ' ~., 2.5 Grams of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-. . ~ ,. . .
hexyloxymethylpiperidine hydrochloride were formulated into capsules according to the procedure described in Example 9.
There was thus obtained a batch o 1000 capsules having a concentration of active ingredients oE 2.5 mg. capsule.
Parenteral Products 0.5 Gram of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine hydrochloride was formulated into ;
ampuls according to the procedure described in Example 9.
There was thus obtained a batch of 1000 ampuls having a concentration of active ingredient 0.5 mg/5ml.
Suppositories 10.0 Grams o 1-(3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpiperidine hydrochloride were ormulated into ~
suppositories according to the procedure described in Example 9. .
The total weight of each suppository was 250.0 mg.
Claims (21)
1. A process for the preparation of a compound of the general formula (I) or an acid addition salt thereof wherein the Alk is straight chain alkylene containing 2 to 4 carbon atoms; Ar and Ar' are phenyl; Ar" is phenyl, pyridyl or thienyl; X is hydrogen or halogen; R is hydrogen, and alkyl radical containing from 1 to 4 carbon atoms or an alkanoyl radical containing from 2 to 5 carbon atoms which is characterized by:
a) reacting a compound of the general formula (II) wherein Alk is defined as above or is wherein the free valence of the carbonyl is attached to the nitrogen and Alk' is alkylene of 1 to 3 carbon atoms, Alkyl is a radical of 1 to 4 carbon atoms and Ar, Ar', Ar" and X are defined as above with a suitable reducing agent in the presence of an organic solvent to give a compound of the general formula (III) wherein Alk, Ar, Ar', Ar" and X are defined as beore with the proviso that 1) when a compound of formula I in which R is an alkanoyl radical is desired the compound of for-mula III is esterified with a suitable anhydride in a basic medium to give the desired ester of formula I and 2) when a compound of formula I in which R is an alkyl radical is desired the compound of formula III can be treated with sodium hydride in a suit-able solvent and further treated with an alkyl halide to give the desired ether of formula I or b) reacting a compound of the general formula wherein Alk, Ar, Ar', Ar" are defined as before and Z is chlorine or bromine with a compound of the general formula wherein R and X are defined as before in a suit-able inert solvent and in the presence of an acid acceptor.
a) reacting a compound of the general formula (II) wherein Alk is defined as above or is wherein the free valence of the carbonyl is attached to the nitrogen and Alk' is alkylene of 1 to 3 carbon atoms, Alkyl is a radical of 1 to 4 carbon atoms and Ar, Ar', Ar" and X are defined as above with a suitable reducing agent in the presence of an organic solvent to give a compound of the general formula (III) wherein Alk, Ar, Ar', Ar" and X are defined as beore with the proviso that 1) when a compound of formula I in which R is an alkanoyl radical is desired the compound of for-mula III is esterified with a suitable anhydride in a basic medium to give the desired ester of formula I and 2) when a compound of formula I in which R is an alkyl radical is desired the compound of formula III can be treated with sodium hydride in a suit-able solvent and further treated with an alkyl halide to give the desired ether of formula I or b) reacting a compound of the general formula wherein Alk, Ar, Ar', Ar" are defined as before and Z is chlorine or bromine with a compound of the general formula wherein R and X are defined as before in a suit-able inert solvent and in the presence of an acid acceptor.
2. The process according to claim 1 (a) wherein the reducing agent used is lithium aluminum hydride.
3. The process according to claim 1 (a) for the pre-paratlon of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-piperidinemeth-anol which is characterized by reacting ethyl 1-(3,3,3-triphenyl-propionyl)-4-phenyl-4-piperidine carboxylate with lithium alum-inum hydride.
4. The process according to claim 1 (a) for the pre-paration of 1-[3,3-diphenyl-3-(2-pyridyl)propyl]-4-phenyl-4-pip-eridinemethanol which is characterized by reacting ethyl 1-[3,3-diphenyl-3-(-pyridyl)propyl]-4-phenyl-4-piperidinecarboxylate with lithium aluminum hydride.
5. The process according to claim 1 (a) for the pre-paration of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-acetoxymethyl-piperidine which is characterized by reacting 1-(3,3,3-triphenyl-propy)-4-phenyl-4-piperidinemethanol with acetic anhydride.
6. The process according to claim 1 (a) for the pre-paration of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-methoxymethyl-piperidine which is characterized by reacting 1-(3,3,3-triphenyl-propyl)-4-phenyl-4-piperidinemethanol with sodium hydride and further reacting this mixture with methyl iodide.
7. The process according to claim 1 (a) for the pre-paration of 1-(3,3,3-triphenylpropyl)-4-(4-chlorophenyl)-4-pi-peridinemethanol which is characterized by reacting 1-(3,3,3-tri-phenylpropionyl)-4-(4-chlorophenyl)-4-piperidinecarboxylic acid ethyl ester with lithium aluminum hydride.
8. The process according the claim 1 (b) for the pre-paration of 1-(3,3,3 triphenylpropyl)-4-phenyl-4-piperidine-methanol which is characterized by reacting 3,3,3-triphenylpro-pylchloride with 4-phenyl-4-piperidinemethanol hydrochloride.
9. A compound of the formula (I) or an acid addition salt thereof wherein the Alk is straight chain alkylene containing 2 to 4 carbon atoms; Ar and Ar' are phenyl; Ar" is phenyl, pyridyl or thienyl; X is hydrogen or halogen; R is hydrogen, alkyl radical containing from 1 to 4 carbon atoms or alkanoyl radical containing from 2 to 5 carbon atoms, whenever prepared by the process of claim 1 or 2.
10. 1-(3,3,3-triphenylpropyl)-4-phenyl-4-piperidine-methanol, whenever prepared by the process of claim 3.
11. 1-[3,3-diphenyl-3-(2-pyridyl)propyl]-4-phenyl-4-piperidinemethanol, whenever prepared by the process of claim 4.
12. 1-(3,3,3-triphenylpropyl)-4-phenyl-4-acetoxymeth-ylpiperidine, whenever prepared by the process of claim 5.
13. 1-(3,3,3-triphenylpropyl)-4-phenyl-4-methoxymeth-ylpiperidine, whenever prepared by the process of claim 6.
14. 1-(3,3,3-triphenylpropyl)-4-(4-chlorophenyl)-4-piperidinemethanol, whenever prepared by the process of claim 7.
15. 1-(3,3,3-triphenylpropyl)-4-phenyl-4-piperidine-methanol, whenever prepared by the process of claim 8.
CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
16. A process for the preparation of a compound of the general formula (I) or an acid addition salt thereof wherein the Alk is straight chain alkylene containing 2 to 4 carbon atoms; Ar and Ar' are phenyl; Ar" is phenyl, pyridyl or thienyl; X is hydrogen or halogen; R is hydrogen, an alkyl radical containing from 1 to 4 carbon atoms, a hexyl radical or an alkanoyl radical contain-ing from 2 to 5 carbon atoms which is characterized by:
a) reacting a compound of the general formula (XI) wherein Alk is defined as above or is wherein the free valence of the carbonyl is attached to the nitrogen and Alk' is alkylene of 1 to 3 carbon atoms, Alkyl is a radical of 1 to 4 carbon atoms and Ar, Ar', Ar" and X are defined as above with a suitable reducing agent in the presence of an organic solvent to give a compound of the general formula (III) wherein Alk, Ar, Ar', Ar" and X are defined as before with the proviso that 1) when a compound of formula I in which R
is an alkanoyl radical is desired the com-pound of formula III is esterified with a suitable anhydride in a basic medium to give the desired ester of formula I and 2) when a compound of formula I in which R
is an alkyl radical containing from 1 to 4 carbon atoms or a hexyl radical is desired the compound of formula III can be treated with sodium hydride in a suitable solvent and further treated with an alkyl halide to give the desired ether of formula I or b) reacting a compound of the general formula wherein Alk, Ar, Ar', Ar" are defined as before and Z is chlorine or bromine with a compound of the general formula wherein X is defined as before and R is hydrogen, an alkyl radical containing from 1 to 4 carbon atoms or an alkanoyl radical containing from 2 to 5 carbon atoms, in a suitable inert solvent and in the presence of an acid acceptor, or c) reacting a compound of the general formula wherein Alk, Ar, Ar', Ar" and X are defined as before with sodium hydride in a suitable solvent to give a compound of the formula wherein Alk, Ar, Ar', Ar" and X are defined as before and then further treating this compound with a hexyl halide to give a compound of formula I or an acid addition salt thereof.
a) reacting a compound of the general formula (XI) wherein Alk is defined as above or is wherein the free valence of the carbonyl is attached to the nitrogen and Alk' is alkylene of 1 to 3 carbon atoms, Alkyl is a radical of 1 to 4 carbon atoms and Ar, Ar', Ar" and X are defined as above with a suitable reducing agent in the presence of an organic solvent to give a compound of the general formula (III) wherein Alk, Ar, Ar', Ar" and X are defined as before with the proviso that 1) when a compound of formula I in which R
is an alkanoyl radical is desired the com-pound of formula III is esterified with a suitable anhydride in a basic medium to give the desired ester of formula I and 2) when a compound of formula I in which R
is an alkyl radical containing from 1 to 4 carbon atoms or a hexyl radical is desired the compound of formula III can be treated with sodium hydride in a suitable solvent and further treated with an alkyl halide to give the desired ether of formula I or b) reacting a compound of the general formula wherein Alk, Ar, Ar', Ar" are defined as before and Z is chlorine or bromine with a compound of the general formula wherein X is defined as before and R is hydrogen, an alkyl radical containing from 1 to 4 carbon atoms or an alkanoyl radical containing from 2 to 5 carbon atoms, in a suitable inert solvent and in the presence of an acid acceptor, or c) reacting a compound of the general formula wherein Alk, Ar, Ar', Ar" and X are defined as before with sodium hydride in a suitable solvent to give a compound of the formula wherein Alk, Ar, Ar', Ar" and X are defined as before and then further treating this compound with a hexyl halide to give a compound of formula I or an acid addition salt thereof.
17. A process for the preparation of a compound of the general formula (I) or an acid addition salt thereof wherein the Alk is straight chain alkylene containing 2 to 4 carbon atoms; Ar and Ar' are phenyl;
Ar" is phenyl, pyridyl or thienyl; X is hydroyen, or halogen;
and R is hexyl which is characterized by reacting a compound of the general formula wherein Alk, Ar, Ar', Ar" and X are defined as before with sodium hydride in a suitable solvent to give a compound of the formula wherein Alk, Ar, Ar', Ar" and X are defined as before and then further treating this compound with a hexyl halide to give a compound of formula I or an acid acldtion salt thereof.
Ar" is phenyl, pyridyl or thienyl; X is hydroyen, or halogen;
and R is hexyl which is characterized by reacting a compound of the general formula wherein Alk, Ar, Ar', Ar" and X are defined as before with sodium hydride in a suitable solvent to give a compound of the formula wherein Alk, Ar, Ar', Ar" and X are defined as before and then further treating this compound with a hexyl halide to give a compound of formula I or an acid acldtion salt thereof.
18. A process according to claim 17 for the prepara-tion of 1-(3,3,3-triphenylpropyl)-4-phenyl-4-hexyloxymethylpip-eridine, or an acid addition salt thereof, which is characterized by reacting sodium 1-(3,3,3-triphenylpropyl)-4-phenyl-4-piperid-inemethoxide with hexyl bromide.
19. A compound of the general formula (I) or an acid addition salt thereof wherein the Alk is straight chain alkylene containing 2 to 4 carbon atoms; Ar and Ar' are phenyl; Ar" is phenyl, pyridyl or thienyl; X is hydrogen or halogen; R is hydrogen, an alkyl radical containing from 1 to 4 carbon atoms, a hexyl radical or an alkanoyl radical contain-ing from 2 -to 5 carbon atoms, whenever prepared by the process of claim 16.
20. A compound of the general formula (I) or an acid addition salt thereof wherein the Alk is straight chain alkylene containing 2 to 4 carbon atoms; Ar and Ar' are phenyl; Ar" is phenyl, pyridyl or khienyl; X is hydrogen, or halogen; and R is hexyl, whenever prepared by the process of claim 17.
21. 1-(3,3,3-Triphenylpropyl)-4-phenyl-4-hexyloxy-methylpiperidine, or an acid addition salt thereof, whenever prepared by the process of claim 18.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/568,439 US3998832A (en) | 1975-04-16 | 1975-04-16 | Anti-diarrheal compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1079734A true CA1079734A (en) | 1980-06-17 |
Family
ID=24271294
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA250,373A Expired CA1079734A (en) | 1975-04-16 | 1976-04-15 | 1-(3,3,3,-triarylpropyl)-4-phenyl-4-piperidinemethanols |
| CA250,355A Expired CA1072089A (en) | 1975-04-16 | 1976-04-15 | 1,1,1 triaryl alkylamines |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA250,355A Expired CA1072089A (en) | 1975-04-16 | 1976-04-15 | 1,1,1 triaryl alkylamines |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US3998832A (en) |
| JP (2) | JPS51131880A (en) |
| AR (3) | AR211859A1 (en) |
| AT (3) | AT347463B (en) |
| AU (2) | AU499878B2 (en) |
| BE (2) | BE840797A (en) |
| CA (2) | CA1079734A (en) |
| CH (5) | CH614448A5 (en) |
| DE (2) | DE2616619A1 (en) |
| DK (2) | DK174776A (en) |
| EG (1) | EG12409A (en) |
| ES (3) | ES447011A1 (en) |
| FI (2) | FI761042A (en) |
| FR (2) | FR2307530A1 (en) |
| GB (2) | GB1537880A (en) |
| GR (2) | GR58248B (en) |
| HU (1) | HU173012B (en) |
| IE (2) | IE42977B1 (en) |
| IL (2) | IL49424A (en) |
| NL (2) | NL7603641A (en) |
| NO (2) | NO761304L (en) |
| NZ (1) | NZ180612A (en) |
| OA (1) | OA05304A (en) |
| PH (1) | PH11412A (en) |
| PT (2) | PT65017B (en) |
| SE (2) | SE7604476L (en) |
| ZA (2) | ZA761681B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4485109A (en) * | 1982-05-07 | 1984-11-27 | E. I. Du Pont De Nemours And Company | 4-Aryl-4-piperidinecarbinols |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4086227A (en) * | 1975-04-16 | 1978-04-25 | G. D. Searle & Co. | Novel anti-diarrheal 4-azatricyclo[4.3.1.13,8 ] undecane derivatives |
| ES463284A2 (en) * | 1976-10-18 | 1978-07-16 | Searle & Co | 1-(3,3,3-triarylalkyl)-4-phenyl-piperidine-methanol ethers |
| US4069223A (en) * | 1977-05-02 | 1978-01-17 | G. D. Searle & Co. | 4-Aminomethyl-1-(3,3,3-triarylpropyl)-4-arylpiperidine and derivatives thereof |
| US4116963A (en) * | 1977-05-23 | 1978-09-26 | G.D. Searle & Co. | 3,3,3-triarylalkyl-4-phenylalkyl-4-hydroxy piperidines and related compounds |
| US4194045A (en) * | 1977-12-27 | 1980-03-18 | G. D. Searle & Co. | 1-(3,3-Diaryl-3-oxadiazolalkyl)-4-phenyl-4-piperidinomethanols and related compounds |
| US4203990A (en) * | 1979-04-30 | 1980-05-20 | G. D. Searle & Co. | Anti-diarrheal 2-substituted quinuclidines |
| US4203989A (en) * | 1979-04-30 | 1980-05-20 | G. D. Searle & Co. | Anti-diarrheal diaryl-(1-azabicyclo(2.2.2)octan-2-yl)-alkanols and related compounds |
| US5962477A (en) * | 1994-04-12 | 1999-10-05 | Adolor Corporation | Screening methods for cytokine inhibitors |
| US6190691B1 (en) | 1994-04-12 | 2001-02-20 | Adolor Corporation | Methods for treating inflammatory conditions |
| US5849761A (en) * | 1995-09-12 | 1998-12-15 | Regents Of The University Of California | Peripherally active anti-hyperalgesic opiates |
| US6573282B1 (en) | 1995-09-12 | 2003-06-03 | Adolor Corporation | Peripherally active anti-hyperalgesic opiates |
| US5889038A (en) * | 1996-03-20 | 1999-03-30 | Children's Hospital | Methods and products for treating diarrhea and scours: use of clotrimazole and related aromatic compounds |
| CA2881935A1 (en) * | 2012-08-15 | 2014-02-20 | Glaxo Group Limited | Process for preparing a 1-(2-haolethyl)-4-piperidine carboxylate intermediate useful in the synthesis of umeclidinium bromide |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2604473A (en) * | 1950-07-17 | 1952-07-22 | Schering Corp | Propylamine type antihistamines |
| GB1125112A (en) * | 1966-01-07 | 1968-08-28 | Science Union & Cie | New derivatives of diazabicyclo-decane and process for preparing them |
| US3917615A (en) * | 1974-04-01 | 1975-11-04 | Searle & Co | 1,1-Diaryl-1-oxadiazol-alkylamines |
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1975
- 1975-04-16 US US05/568,439 patent/US3998832A/en not_active Expired - Lifetime
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1976
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- 1976-04-07 NL NL7603641A patent/NL7603641A/en not_active Application Discontinuation
- 1976-04-12 EG EG76212A patent/EG12409A/en active
- 1976-04-14 ES ES447011A patent/ES447011A1/en not_active Expired
- 1976-04-14 AR AR262892A patent/AR211859A1/en active
- 1976-04-14 NO NO761304A patent/NO761304L/no unknown
- 1976-04-14 IL IL49424A patent/IL49424A/en unknown
- 1976-04-14 IL IL49422A patent/IL49422A/en unknown
- 1976-04-14 AR AR262893A patent/AR216438A1/en active
- 1976-04-14 DK DK174776A patent/DK174776A/en unknown
- 1976-04-14 DK DK173976A patent/DK173976A/en active IP Right Grant
- 1976-04-14 NO NO761303A patent/NO761303L/no unknown
- 1976-04-14 ES ES447010A patent/ES447010A1/en not_active Expired
- 1976-04-15 CH CH175379A patent/CH614448A5/en not_active IP Right Cessation
- 1976-04-15 FR FR7611237A patent/FR2307530A1/en active Granted
- 1976-04-15 BE BE166202A patent/BE840797A/en unknown
- 1976-04-15 IE IE815/76A patent/IE42977B1/en unknown
- 1976-04-15 PT PT65017A patent/PT65017B/en unknown
- 1976-04-15 AU AU13043/76A patent/AU499878B2/en not_active Expired
- 1976-04-15 NZ NZ180612A patent/NZ180612A/en unknown
- 1976-04-15 NL NL7604063A patent/NL7604063A/en not_active Application Discontinuation
- 1976-04-15 FI FI761042A patent/FI761042A/fi not_active Application Discontinuation
- 1976-04-15 AT AT278976A patent/AT347463B/en not_active IP Right Cessation
- 1976-04-15 SE SE7604476A patent/SE7604476L/en not_active Application Discontinuation
- 1976-04-15 AT AT279076A patent/AT348525B/en not_active IP Right Cessation
- 1976-04-15 PT PT65016A patent/PT65016B/en unknown
- 1976-04-15 CA CA250,373A patent/CA1079734A/en not_active Expired
- 1976-04-15 CH CH485276A patent/CH614197A5/en not_active IP Right Cessation
- 1976-04-15 JP JP51043020A patent/JPS51131880A/en active Pending
- 1976-04-15 FR FR7611236A patent/FR2307535A1/en active Granted
- 1976-04-15 AU AU13042/76A patent/AU502260B2/en not_active Expired
- 1976-04-15 CH CH485376A patent/CH626879A5/en not_active IP Right Cessation
- 1976-04-15 IE IE816/76A patent/IE42978B1/en unknown
- 1976-04-15 JP JP51043021A patent/JPS51127054A/en active Pending
- 1976-04-15 GB GB15542/76A patent/GB1537880A/en not_active Expired
- 1976-04-15 GB GB15541/76A patent/GB1540103A/en not_active Expired
- 1976-04-15 GR GR50559A patent/GR58248B/en unknown
- 1976-04-15 CA CA250,355A patent/CA1072089A/en not_active Expired
- 1976-04-15 SE SE7604475A patent/SE7604475L/en unknown
- 1976-04-15 OA OA55799A patent/OA05304A/en unknown
- 1976-04-15 HU HU76SE00001827A patent/HU173012B/en unknown
- 1976-04-15 DE DE19762616619 patent/DE2616619A1/en not_active Withdrawn
- 1976-04-15 BE BE166203A patent/BE840798A/en unknown
- 1976-04-15 DE DE19762616616 patent/DE2616616A1/en not_active Withdrawn
- 1976-04-15 GR GR50558A patent/GR58247B/en unknown
- 1976-04-15 FI FI761041A patent/FI761041A/fi not_active Application Discontinuation
- 1976-04-15 ZA ZA762292A patent/ZA762292B/en unknown
- 1976-04-19 PH PH18337A patent/PH11412A/en unknown
- 1976-11-29 AR AR265651A patent/AR208862A1/en active
-
1977
- 1977-05-30 ES ES459283A patent/ES459283A1/en not_active Expired
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1978
- 1978-01-17 AT AT32178A patent/AT347952B/en not_active IP Right Cessation
-
1981
- 1981-02-12 CH CH94781A patent/CH629190A5/en not_active IP Right Cessation
- 1981-02-12 CH CH94881A patent/CH629191A5/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4485109A (en) * | 1982-05-07 | 1984-11-27 | E. I. Du Pont De Nemours And Company | 4-Aryl-4-piperidinecarbinols |
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